Targeting RNA Splicing in Glioma

胶质瘤中的靶向 RNA 剪接

基本信息

批准号：
10530184
负责人：
Shi-Yuan Cheng
金额：
$ 49.06万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10530184
关键词：
Address Affect Alternative Splicing Antisense Oligonucleotides Biological Biological Models Biological Process CDKN2A gene Cell model Classification Clinical Clustered Regularly Interspaced Short Palindromic Repeats DNA Sequence Alteration Data Set Development Disease Duchenne muscular dystrophy Eukaryota Event Evolution Genome Genotype Glioma Goals Growth Human Human Engineering Knowledge Maintenance Malignant Neoplasms Mediating Mediator of activation protein Modeling Molecular Mutation Oligonucleotides Oncogenic PTEN gene Pathway interactions Patients Phenotype Prognosis Property Protein Binding Domain Protein Isoforms Protein Splicing Proteins Proteome RNA Splicing RNA-Binding Proteins Research Research Project Grants Spliced Genes Technology Testing Therapeutic Therapeutic Intervention Transcription Process Tumor Biology Tumorigenicity Xenograft Model avatar models base clinically relevant differential expression driver mutation epidermal growth factor receptor VIII human disease induced pluripotent stem cell innovation malignant phenotype methylome molecular subtypes novel patient prognosis programs protein expression stem-like cell transcriptome transcriptome sequencing treatment response tumor tumor xenograft

项目摘要

Targeting RNA Splicing in Glioma RNA alternative splicing (AS) is an evolutionally conserved co-transcriptional process, regulates transcriptome and proteome landscapes in eukaryotes, and in human diseases such as cancer. Unlike the numerous studies that have been conducted for characterizing glioma genomes, transcriptomes, methylomes, and proteomes, little has been done to associate glioma driver mutations with AS programs and evaluate the impact of dysregulated AS on cancer malignancy. Our analyses of AS in three glioma patient RNA-seq datasets indicate two AS glioma subtypes that show associations with WHO tumor grade, glioma driver mutations, and patient prognosis. Utilizing a human induced pluripotent stem cell (hiPSC)- derived glioma “avatar” model and clinical glioma models, we show that IDH1R132H/WT or PTEN-/- /CDKN2A/2B-/-/TertpC228T/WT/EGFRvIII genotypes influence subtype-associated AS programs. Two subsets of RBPs that affect RNA splicing are differentially associated with these two AS glioma subtypes. Expression of subtype-associated RBPs or AS isoforms also affected AS events and growth of glioma stem-like cells (GSCs). In this research project, we plan to leverage our previous contributions, existing research program, recent findings, newly established glioma avatar models, cutting-edge CRISPR editing technology, and outstanding scientific premise to study whether glioma mutations influence AS programs and how RNA binding proteins (RBPs) and AS gene isoforms contribute to glioma tumor biology. AS programs will also be exploited for therapeutic intervention in treating gliomas. This project will address key gaps in our understanding of the relationships between glioma driver mutations and tumor-associated AS programs, and test whether targeting RNA splicing constitutes a therapeutic vulnerability to treat gliomas. In addressing these knowledge gaps this research will influence our understanding and treatment of glioma, and in so doing will likely influence the study of other cancers.

靶向神经胶质瘤中的 RNA 剪接 RNA选择性剪接（AS）是一种进化上保守的共转录过程，调节真核生物以及癌症等人类疾病中的转录组和蛋白质组景观。已经进行了大量研究来表征神经胶质瘤基因组、转录组、甲基组和蛋白质组，很少有人将神经胶质瘤驱动突变与 AS 程序联系起来并评估失调的 AS 对癌症恶性肿瘤的影响。我们对三种神经胶质瘤的 AS 进行了分析。患者 RNA-seq 数据集表明两种 AS 神经胶质瘤亚型与 WHO 肿瘤分级相关，神经胶质瘤驱动突变和患者预后利用人类诱导多能干细胞 (hiPSC)。衍生的胶质瘤“阿凡达”模型和临床胶质瘤模型，我们表明 IDH1R132H/WT 或 PTEN-/- /CDKN2A/2B-/-/TertpC228T/WT/EGFRvIII 基因型影响亚型相关的 AS 程序。影响 RNA 剪接的 RBP 与这两种 AS 神经胶质瘤亚型存在差异相关。亚型相关 RBP 或 AS 亚型的表达也影响 AS 事件和神经胶质瘤的生长在这个研究项目中，我们计划利用我们之前的贡献和现有的成果。研究计划、最新发现、新建立的神经胶质瘤化身模型、尖端 CRISPR 编辑研究神经胶质瘤突变是否影响 AS 项目的技术和杰出的科学前提以及 RNA 结合蛋白 (RBP) 和 AS 基因亚型如何促进神经胶质瘤肿瘤生物学。该项目还将用于治疗神经胶质瘤的治疗干预。我们对神经胶质瘤驱动突变与肿瘤相关突变之间关系的理解存在关键差距 AS 程序，并测试靶向 RNA 剪接是否构成治疗脆弱性为了解决这些知识差距，这项研究将影响我们对神经胶质瘤的理解和治疗。神经胶质瘤的研究，这样做可能会影响其他癌症的研究。